THE PEPTIDE REVOLUTION

01-October-2017

RAJGOPAL NIDAMBOOR

The word, peptide, originates from ‘peptein,’ the Greek word for ‘pepsis,’ or ‘to digest.’ It was first coined by Hermann Emil Louis Fischer, a German chemist and Nobel laureate, at the beginning of the last century, evidencing that peptides are characteristically generated by our gut. Peptides are, in reality, more than representative of our digestive process or natural biological bustle — they are, in essence, our molecules of emotions, the emblematic icons of our feelings. They are found in all living organisms; they perform a pivotal role in every form of biological activity.

Our bodies are studded with peptide receptors. For neuroscientist and pharmacologist Candace B Pert, PhD, a pioneer in peptide research, who passed into sunset, four years ago, peptides relate to consciousness operating at a cellular level, typifying the ‘wedding dance’ of each receptor and the exact peptide that binds to it. In her words, "Your subconscious mind is really your body. Peptides are the biochemical correlate of emotion." Her landmark work evidences that our white blood cells [WBCs], which swank loads of the same receptors and chemicals as the brain, are nothing but “bits of the brain floating around the body.” This also draws a parallel for a type of molecular psychology, the true biology of our emotions.

Peptides are formed or synthesised, like proteins, through biological processes, which involve the copying of a specific deoxyribonucleic acid [DNA] sequence into a messenger molecule. This, thereafter, conveys the code for a given peptide, or protein, following which a ‘chain’ of amino acids is coupled together by peptide bonds to shape a single molecule. There are 20 naturally-occurring amino acids and, like strings in a tennis racquet, hooked up to a vast range of diverse molecules. When a molecule encompasses of 2-50 amino acids, it is called a peptide; a larger sequence of more than 50 amino acids is referred to as a protein.

Peptides are found in every cell and tissue; they are involved in an extensive array of essential functions — right from the maintenance of appropriate biological concentration and activity levels to achieving homeostasis and maintaining health. Peptides act like hormones — in other words, they don the role of biologic messengers disseminating information from one tissue through the blood to another. There are two common forms of hormones in our body — peptide and steroid hormones. The former are produced in the glands, stomach, intestines and brain. To cull a classical example — one could think of the peptide hormones involved in blood glucose regulation, including insulin, glucagon-like-peptide-1 [GLP-1] and glucagon, besides ghrelin, a peptide that regulates our appetite.

Like the good, old Eastern adage that before the word came into existence, there was sound, there were molecules much before the emergence of life on Earth. This is often referred to as the elemental soup. A few specialised molecules began self-replicating — this, it is believed, initiated the biochemical process for the first organisms to come into being. This is, of course, not as simple as it sounds. It is complex and also mysterious, although research suggests that ribozymes — ribonucleic acid [RNA] enzymes — acted as catalysts and galvanised such early blueprints into action, activating the materialisation of life from a plethora of molecules. Controversy dogs the hypothesis, all right, because it would have takes ages for arbitrarily generated RNA molecules to develop adequately and attain the contemporary altitude of sophistication.

New research has endeavoured to bridge the gap, somewhat. Studies have found that all enzymes have almost analogous cores that can be extracted to produce ‘molecular fossils.’ They are called Urzymes — ‘ur,’ for the initial or inventive. The other parts are suggested to be variations introduced later, or when evolution began. Protagonists believe that there are two Urzymes. The assertion is also as proximal as modern research can corroborate vis-à-vis the ancient puzzle of enzymes that may have populated our planet, aeons ago. This is not all. Latest findings evidence that Urzymes could have evolved from the most simple of ancestors — petite proteins called peptides.

The inference, in the fullness of time, as researchers observe, such peptides jointly evolved with the RNA to generate more complex life forms. It is, again, early days for the premise to be cuddled by the sceptics. Yet, one fact remains — that the whole idea may trigger new research to embrace polymerases — enzymes that actually assemble the RNA molecule. This would be the highest point, a culmination, or climax for science — to finding and establishing the Urzyme credo which, perhaps, ‘engineered’ the purpose and context as regards the long-standing ‘coming-of-life’ question.

There is new, compelling evidence too to suggest that peptides play a key role in the regulation of body weight and energy metabolism — and, in conveying our feelings and emotions. What’s more, a large body of scientific work celebrates the versatile roles that peptides perform in the regulation of blood volume and arterial pressure, not to speak of diuretic, vasodilatory and antimitogenic functions — in other words, the regulation of heart, kidney, and endocrine homeostasis. Advanced research corroborates the function peptides exert in the regulation of fatty acid metabolism too.

Conventional medicine, notwithstanding its stupendous advance, is not yet perfect as perfect can be. This holds good for ‘perfect’ drugs too, primarily because of their simple or composite chemistry involved in the making of a great drug, or ‘dumping’ a drug that has lost its sheen, or did not live up to its earlier promise. It should be remembered that most of the molecules in our body are proteins — they exert a pivotal role in areas such as digestion and oxygen transport to all cells of the body. Each drug, or medicine, is keyed to a specific target protein. For example, a drug may block the action of a protein, which is made by a particular virus. There is a ‘spot’ on the protein which is important for the virus to function. The drug which is prescribed to treat the illness travels and lodges precisely in that area, impeding the protein ‘to death’ in its line. The only downside, at times, is it does not lodge strongly enough and may, over time, get kayoed. This will call for a higher dosage of the drug to keep the protein under check.

Now, the big question. Would it not be amazing for us to design peptide medicines in the lab to ‘match’ the ‘dot’ on the virus protein, so that they can lodge firmly on the drug? This will not only reduce the dosage of the drug, but also assist the body to break the peptide down and use its amino acids for a better purpose, long after the virus is sent packing to its doom. What is the raison d’être for such an outcome? Simple — peptides are innate to our body, or physiology. Following their brilliant cameo as medicine, without side-effects, they become food for the system, unlike medicines which are not a natural, innate part of our body.

More recently, medical scientists have used metal complexes to ‘transform’ peptide hormones, positioning their molecular foundation for the development of better medicines that influence the sensation of pain and tumour growth, to highlight a case in point. Researchers have also developed a synthetic peptide — the first in a new class of drugs to treat high blood pressure, heart disease and diabetes. Research has tapped a deficit, no less, in a peptide [apelin] associated with heart failure, pulmonary hypertension and diabetes. This has led to the development of a synthetic version that targets specific pathways in the heart and promotes blood vessel growth.

The synthetic form of apelin is evidenced to be tangibly steady and more effective than the naturally occurring peptide, making futuristic drug therapies exciting. There is also a ‘smart’ peptide that is just as good for your muscles, skin and joints. You know it, don’t you? Gelatine, a tangy, flavoursome jelly. There is yet another exciting prospect in progress. Pert was resolutely determined to bring, at long last, a non-toxic, exceptionally powerful HIV drug [Peptide-T] that she helped discover more than twenty years ago. Pert believed that Peptide-T has the potential to effectively treat, and possibly cure, AIDS. When her dream reaches fruition — it will be a fitting tribute to her ground-breaking work.

There are more than a handful of ‘smart’ peptides in use in medicine already. Certain antibiotics like bacitracin and cyclosporine are, in point of fact, peptides. Cyclosporine helps prevent rejection of the foreign tissue by our body's immune system, after organ transplant. Milk peptides, which are essentially tripeptides, a set of peptides with three amino acids each, as studies testify, also help to keep blood pressure at healthy levels. Leupeptin is, likewise, another tripeptide, used to treat ear infections.

Glutathione is an important peptide found in our bodies too. It helps to clean up free radicals, which are produced during normal activities of our body. These radicals can damage cells, cause pain, paralysis or toxicity. In patients who have low glutathione levels, due to certain illnesses, like AIDS, prescribing glutathione from the outside often helps. However, glutathione gets fully absorbed in the stomach, so it can't be taken as a pill. Instead, a peptide called N-acetylcysteine [NAC] is given as a drug. The body converts this naturally to glutathione. It is mission accomplished.

Yet another peptide that is being tested in labs is delta sleep-inducing peptide [DSIP]. Studies show that it can help people battling to get off their addiction to psychotropic drugs, or alcohol. DSIP helps to combat narcolepsy, a condition in which the patient feels too sleepy throughout the day; it also helps children recovering from the after-effects of chemotherapy.

The list is expanding with more peptides being tested and used against all kinds of illnesses, or disease, including systemic disorders like high blood pressure, diabetes, and cancer, among others. If you are an intrepid medical researcher, or pharmacologist, you’d sure think of making a peptide medicine that would provide the novel edge to the peptide remedial armamentarium now available, or solve a major medical problem, or complex illness — a new therapeutic gift to mankind.